The long-term objective is to understand mechanisms by which Candida albicans disseminates during a fungemia. Our hypothesis is that cell surface molecules of C. albicans (ie., adhesins) account for organ tropism, and pathogenesis and manifestations of disseminated candidiasis. The implication is that C. albicans does not associate with all tissues and depends on host ligand molecules. In addition, the hypothesis implies a C. albicans adhesin/host ligand interaction results in release of substances that in part account for manifestations of disseminated candidiasis. The health related aspects of this work are manifold. These studies will yield significant new insights into host-C. albicans interactions and may lead to novel therapeutic approaches. We will not address all implications of the hypothesis. Instead, the work will focus on interaction of C. albicans with mouse splenic tissue, and more specifically with the exquisite specificity of C. albicans for marginal zone cells within the spleen. We will characterize the fungal adhesin(s) and host ligand(s) molecules involved in marginal zone interaction. The adherence assay used in these studies is called an ex vivo assay that has been used by others to identify homing receptors of lymphocytes and inflammatory cells. We adapted the assay to the study of an infectious disease agent and our preliminary data indicate for the first time that the marginal zone contains its own specific adhesion ligand molecule. The specific aims are as follows. 1) Produce antibodies specific for the adhesin responsible for the binding event. Polyclonal and monoclonal antibodies will be sought. 2) Use immunofluorescence microscopy, immunoelectron microscopy, and flow cytometry to characterize expression of the adhesin(s) on yeast and hyphal forms during in vitro growth and in vivo during pathogenesis of candidiasis. Adhesin-specific antibodies and classical fractionation techniques will be used to isolate, purify and chemically characterize the adhesin(s). 3) The host cell in the marginal zone to which C. albicans binds will be identified and antibodies specific for the host ligand(s) will be generated. Rabbit polyclonal antisera will be raised against mouse splenic stromal fractions containing the ligand, and rats will be used to obtain monoclonal antibodies against the ligand(s). The antibodies will be used to determine distribution of the host ligand(s) in other tissues and determine their effect on pathogenesis. 4) The relationship of the marginal zone adherence to pathogenesis of candidiasis will be studied by pretreating mice with solubilized adhesin(s) and antibodies specific for the ligand(s), and determining the effect of these treatments on distribution of C. albicans in tissues following experimentally induced fungemia. The survival of treated animals infected with C. albicans will be compared with appropriate controls. Focus on the spleen is justified because this organ is an important clearing mechanism of a C. albicans fungemia, yet host cells and fungal adhesins involved have not been identified. The number of individuals who develop splenic candidiasis is increasing and the reasons are not clear. Finally, we developed the techniques and tools to focus on this important host/C. albicans interaction and should be able to fulfill our intended goals.